The present invention generally relates to anxiolytic and anticonvulsant agents, specifically the invention relates to a class of stereospecific benzodiazepine derivatives which possess anxiolytic, anticonvulsant activity with decreased muscle-relaxant, sedative-hypnotic and ataxic side effects.
The most frequently prescribed medication for treatment of anxiety or convulsant disorders (such as phobias, obsessive compulsive disorders) and seizure disorders are benzodiazepines such as diazepam (Valium), triazolam (Halcion), midazolam (Versed), lorazepam (Ativan), chlordiazepoxide (Librium), alprazolam (Xanax), and other benzodiazepine-based medications. However, these benzodiazepine-based medications have side effects such as drowsiness, sedation, motor incoordination, memory impairment, potentiation of effects of alcohol, tolerance and dependence, and abuse potential. Buspirone, tandospirone, and other serotonergic agents have been developed as anxiolytics with a potentially reduced profile of side effects. However, while these medications do show a reduced profile of side effects, they have other characteristics which make them less than ideal for treatment of anxiety disorders. In some cases, these agents cause anxiety before a therapeutic dose can be obtained or require dosing of the drug for several days before a therapeutic effect is seen. Development of anxiolytics with even fewer side effects is desired.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into three main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily; and (3) GABAC receptors, also members of the ligand-gated ion channel superfamily, but their distribution is confined to the retina. Benzodiazepine receptor ligands do not bind to GABAB and GABAC receptors. Since the first cDNAs encoding individual GABAA receptor subunits were cloned, the number of known members of the mammalian family has grown to 21 including α, β, and γ subunits (6α, 4β, 4γ, 1δ, 1ε, 1π, 1θ, and 3ρ).
Subtype assemblies containing an α1 subunit (α1β2γ2) are present in most areas of the brain and are thought to account for 40-50% of GABAA receptors in the rat brain. Subtype assemblies containing α2 and α3 subunits respectively are thought to account for about 25% and 17% GABAA receptors in the rat brain. Subtype assemblies containing an α5 subunit (α5β3γ2) are expressed predominately in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat brain.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine binding site. The benzodiazepine binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which benzodiazepine-based anxiolytic drugs exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BENZODIAZEPINE1 and BENZODIAZEPINE2, on the basis of radioligand binding studies on synaptosomal rat membranes. The BENZODIAZEPINE1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the α1 subunit in combination with a β subunit and γ2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain, as stated.
Two other major populations are the α2β2/3γ2 and α3β2/3γ2/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor population. Pharmacologically this combination appears to be equivalent to the BENZODIAZEPINE2 subtype as defined previously by radioligand binding, although the BENZODIAZEPINE2 subtype may also include certain α5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as benzodiazepine agonists at GABAA/α2, GABAA/α3, and/or GABAA/α5 receptors, will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as benzodiazepine agonists are referred to hereinafter as “GABAA receptor agonists.” The GABAA/α1-selective (α1β2γ2) agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BENZODIAZEPINE1 binding site is mediated through GABAA receptors containing the α1 subunit. Accordingly, it is considered that GABAA/α2, GABAA/α3, and/or GABAA/α5 receptor agonists rather than GABAA/α1 receptors will be effective in the treatment of anxiety or convulsant disorders with a reduced propensity to cause sedation. For example, QH-ii-066 binds with high affinity to GABAA/α5 receptors (Ki<10 nM), intermediate affinity to GABAA/α2 and GABAA/α3 (Ki<50 nM), and lower affinity to GABAA/α1 receptors (Ki>70 nM), unlike diazepam which binds with high affinity to all four diazepam-sensitive GABAA receptors (Ki<25 nM), as disclosed in Huang, et al., J. Med. Chem. 2000, 43, 71-95. Also, agents which are antagonists or inverse agonists at α1 receptors might be employed to reverse sedation or hypnosis caused by α1 agonists.
There are yet further advantages to targeting specific GABA receptors, namely in the treatment of alcohol addiction. Alcohol addiction and dependence remain a significant public health concern, impacting physical and mental well-being, family structure and occupational stability. While advances have been made in the development of novel therapies to treat alcoholism (O'Malley S S, et al., (1992) Arch Gen Psychiatry 49: 881-887; Volpicelli J R, et al., (1992) Arch Gen Psychiatry 49: 876-880; Kranzler H R (2000) Alcohol 35:537-547; Spanagel R, Zieglgansberger (1997) Trends Pharmacol Sci 18:54-59), alcohol-dependent individuals represent a heterogeneous group (Cloninger (1987) Science 236: 410-416; Li T-K, et al. (1991): Molecular and genetic approaches to understanding alcohol-seeking behavior. In Meyer R E, Koob G F, Lewis M J, Paul S P (eds), Neuropharmacology of ethanol. Boston: Birkhauser, pp 107-124; Li T-K (2000): Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol 61: 5-12), and it is unlikely that a single pharmacological treatment will be effective for all alcoholics. Hence, a better understanding of the neuromechanisms which regulate alcohol seeking behaviors and the design of clinically safe and effective drugs that reduce alcohol addiction and dependence remain a high priority (Johnson B A, Ait-Daoud N (2000): Neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Psychopharmacology (Berlin) 149:327-344). While the precise neuromechanisms regulating alcohol-seeking behaviors remain unknown, there is now compelling evidence that the GABAA receptors within the striatopallidal and extended amygdala system are involved in the “acute” reinforcing actions of alcohol (Koob G F et al., (1998) Alcoholism: Clin Exper Res 22:3-9; June et al., 1998c; McBride W J, Li T (1998): Animal models of alcoholism: Neurobiology of high alcohol-drinking behavior in rodents. Critical Reviews in Neurobiology 12(4):339-369). The striatopallidal and extended amygdala system include the subventicular extended amygdala [substantia innominata-ventral pallidum (VP)], shell of the nucleus accumbens, and central nucleus of the amygdala (Heimer et al., 1991; Heimer and Alheid, 1991). Among the potential GABAA receptor isoforms within the VP regulating alcohol-seeking behaviors, GABAA receptors containing the α1 receptor subtype (GABAA1) appear preeminent. Thus, Criswell et al., (1993, 1995) observed that acute alcohol administration selectively enhanced the effects of ionotophoretically applied GABA in the VP (Criswell H E, et al., (1993): Molecular basis for regionally specific action of ethanol on γ-aminobutyric acidA receptors: Generalization to other ligand-gated ion channels. J Pharmacol Exper Ther 267:522-527; Criswell H E, et al (1995): Effect of zolpidem on γ-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions. J Pharmacol Exper Ther 273:525-536). However, no effects were seen in the septum, VTA, and CA1 hippocampus. Further, a positive correlation was observed between alcohol-induced GABA enhancement and [3H] zolpidem binding (an α1 subtype selective agonist). Other investigators have identified a dense reciprocal projection from the VP to the NACC (Nauta H J, et al., (1978a) Neuroscience, 3:189-202; Nauta W J, et al., (1978b) Neuroscience 3: 385-401; Zahm D S and Heimer L (1988) J Comp Neurol 272: 516-535; Groenewegen H J, et al., (1993) Neuroscience 57:113-142), and many of these have been found to be GABA ergic neurons (Mogenson G J, Nielson M A (1983) Brain Res Bulletin 11: 309-314; Kuo H and Chang H T (1992): Ventral-pallidostriatal pathway in the rat brain: A light electron microscopic study. J Comp Neurol 321:626-636; Churchill L, Kalivas P W (1994): A topographical organized GABA projection from the ventral pallidum to the nucleus accumbens in the rat. J Comp Neurol 345:579-595). The NACC is well established as a substrate that regulates the reinforcing properties of abused drugs. Finally, immunohistochemical (Turner J D, Bodewitz G, Thompson C L, Stephenson F A (1993): Immunohistochemical mapping of gamma-aminobutyric acid type-A receptor alpha subunits in rat central nervous system. In: Anxiolytic β-carbolines: from Molecular Biology to the Clinic (D. N. Stephens, ed), pp 29-49 New York: Springer-Verlag; Fritschy J M, Mohler H (1995): GABAA-receptor heterogenetity in the adult rat brain. Differential regional and cellular distribution of seven major subunits. J Comp Neurol 359:154-194) and in situ hybridization studies (Churchill et al., 1991; Wisden et al., 1992; Duncan et al., 1995) have demonstrated that the VP contains one of the highest concentrations of mRNA encoding the α1 subunit in the CNS. These findings, together with pharmacological studies suggesting the VP plays a role in reward-mediated behaviors of psychostimulants and opiates (Hubner C B, Koob G F (1990) Brain Res 508:20-29; Napier and Chrobak, 1992; Gong et al., 1996; 1997), suggest a possible role of the VP-α1 receptors in the euphoric properties of alcohol.
Since the compounds of the present invention exhibit increased agonist efficacy at only a few GABAA types of receptors and/or selective efficacy at one or more ion channels and have been shown to be effective in animal models of anxiety and seizures, with reduced severity and/or incidence of side effects, they are useful in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, general anxiety disorder, attention deficit disorders, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder, neuroses, convulsions; migraine; depressive or bipolar disorders, for example single episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder, psychotic disorders including schizophrenia, alcoholism and emesis, with reduced side effects.